KR20140040218A - Indoleamine derivatives for the treatment of central nervous system diseases - Google Patents

Abstract

Indoleamine derivatives of formula (IA), and pharmaceutically acceptable salts and solvates thereof, wherein R ¹ is benzyl unsubstituted or substituted with a halogen atom, —OH, or C ₁ -C ₃ -alkyl; Or phenylsulfonyl unsubstituted or substituted with a halogen atom, -OH or C ₁ -C ₃ -alkyl in the phenyl ring, G ¹ represents phenoxyalkyl, heteroaryloxyalkyl- or heterocyclyloxyalkyl-pipe Represents a azine moiety. The compounds may be useful for the treatment and / or prevention of central nervous system disorders.

Description

Indoleamine derivatives for the treatment of diseases of the central nervous system {INDOLEAMINE DERIVATIVES FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISEASES}

The present invention relates to novel indoleamine derivatives having affinity for dopaminergic, serotonergic and adrenergic receptors, and serotonin transporters, pharmaceutical compositions containing them and their use. The compounds may be useful for the treatment of central nervous system (CNS) diseases such as schizophrenia, bipolar affective disorders, depression, anxiety disorders, sleep disorders or Alzheimer's disease.

CNS disorders are considered a global medical problem. Many people suffering from such diseases continue to grow, especially in developed and developing countries.

Of all mental disorders, schizophrenia, bipolar affective disorder, depression, anxiety, sleep disorders and addiction are the main ones. Important nervous system disorders are Alzheimer's disease, Parkinson's disease, epilepsy and different pain disorders.

Antipsychotic drugs are the major treatments for schizophrenia and are divided into two major classes based on their responsibility for causing neurological side effects after long-term treatment. Typical antipsychotic drugs such as chlorpromazine and haloperidol cause a variety of extrapyramidal side effects (EPS), including Parkinson-like symptoms and delayed dyskinesia after repeated administration. Repeated treatment with so-called typical antipsychotic drugs such as clozapine, risperidone, olanzapine, quetapin, ziprasidone and aripiprazole is associated with a lower incidence of nervous system side effects. Typical antipsychotics lower positive symptoms but do not lower negative symptoms and cognitive impairment. In humans there is an increase in plasma prolactin levels and potentially weight gain leading to the development of metabolic syndrome. Typical antipsychotic drugs effectively lower positive symptoms and, to some extent, negative symptoms and cognitive confusion, resulting in less severe EPS. Typical antipsychotic drugs differ in their propensity to raise plasma prolactin levels in humans. Typical antipsychotic drugs block dopamine D2 receptors in the mesolimbic and medulla strata. This mechanism is responsible for psychotropic effects (decreased benign symptoms) and induction of EPS. Clinical support for the dopamine hypothesis of antipsychotic drug action is provided by PET discovery with high dopamine D2 receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments. Patients with good response show more than 65% dopamine D2 receptor occupancy (Nord M, Farde L. Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neuroscience & Therapeutics. 2010; 17:97.). The occurrence of EPS seems to be associated with a high occupancy of the dopamine D2 receptor (about 80%). Typical antipsychotics, so-called second-generation antipsychotic drugs, have been clinically approved for the treatment of psychosis and mania. Each drug has a unique pharmacokinetic and pharmacokinetic profile. Some of the typical antipsychotic drugs have additional antidepressant, antianxiety or hypnotic profiles (Schwartz TL, Stahl SM, CNS Neurosci. Ther .; 17 (2), 110-7, 2011). Typical antipsychotic drugs typically have strong serotonin 5-HT2A receptor antagonism with respect to the weaker dopamine D2 receptor antagonism. These pharmacodynamic properties are the basis of " visionality " (Meltzer HY, Neuropsychopharmacology ; 1, 193-6, 1989). The antagonism of the 5-HT2A receptor probably avoids EPS by allowing more dopamine activity and neurotransmission to occur in the cortical striatum. The same mechanism may enable some improvement of negative symptoms and 5-HT2 antagonism in the gray funnel pathway may help to avoid hyperprolactinemia (Schwartz TL, Stahl SM, CNS Neurosci. Ther .; 17 (2), 110-7, 2011).

Dopamine functional D2 receptors are important biological targets for antipsychotic treatment. It is recognized that blockade of these receptors in the mesolimbic system is responsible for the antipsychotic activity of neuroleptics, especially for the prevention of benign symptoms. All antipsychotic drugs currently used exhibit at least moderate affinity for the dopamine D2 receptor. However, if not compensated by partial agonism for these receptors or by affecting other receptors (5-HT2A, 5-HT1A, alpha2c), blockade of these receptors in the chondrocyte system is hyperprolactinosis. Within the nodual papillary pathway of, it may be the cause of extrapyramidal disorders such as drug-induced Parkinson's disease (Miyamoto S. et al., Mol. Psychiatry; 10 (1), 79-104, 2005).

Dopaminergic D3 receptors are localized in the marginal cortex, so preferential blockade of these receptors provides locally selective antidopaminergic activity. This leads to an increase in the effect on reducing the positive symptoms of schizophrenia that escapes the blockage of the system extrapyramidally, thus lowering the risk of major side effects such as pseudoparkinson syndrome. In addition, some preclinical data suggest that D3 dopamine receptor antagonism is more effective in reducing negative symptoms of schizophrenia and improves working memory (Gray, JA, Roth BL; Schizophr. Bull .; 33 (5, 1100). -19, 2007).

Serotonin functional neurons interact with dopamine functional neurons. The antagonistic activity of antipsychotics against the serotonin-functional receptor 5-HT2A type can stimulate dopamine release extracorporeally in the nodular papillary and frontal cortex, but not in the cerebral limbic system, which is responsible for D2 receptor blockade. Undesired extracorporeal induced by it may result in an increase in symptoms and hyperprolactinosis, and without an increase in positive symptoms, may lead to an increased effect of the drug on some negative symptoms of schizophrenia. The high affinity of the 5-HT1A receptor, which is higher than the D2 receptor, is believed to be one of the reasons for the atypical nature of the second generation antipsychotics. Similar effects to those caused by blockade of the 5-HT2A receptor are achieved by stimulation of serotonin receptor type 5-HT1A (aripiprazole, ziprasidone). Stimulation of the 5-HT1A receptor, in particular in the drug's safety profile, participates in antipsychotic effects in combination with D2 receptor blockade and is also believed to be beneficial for cognitive symptoms and fighting mood in schizophrenia (Kim D. et al., Neurotherapeutics, 6 (1), 78-85, 2009).

Despite the improvements made in the development of antidepressants, there is a clinical need that is still clearly unmet for both efficacy and side effects. This need is in the range of efficacy in the treatment of resistant patients (about 30%) to improve onset of reduction of side effects such as sexual dysfunction, gastrointestinal events, sedation, weight gain. There are several attempts to improve current pharmacological means of regulating biogenic amine neurotransmission by combining mechanisms that result in improved efficacy or very few side effects, or alternatively by selectively stimulating / blocking receptor subtypes. do. One of them retains the benefits associated with selective serotonin reuptake inhibitors (SSRIs) (blockers of serotonin transporters), but improves efficacy by adding additional mechanisms associated with blockade of 5-HT2A or 5-HT2C receptors. Combination therapy that attempts to enhance or reduce side effects (Millan M., Neurotherapeutics, 6 (1), 53-77, 2009). 5-HT2A receptor antagonists administered alone can produce antidepressant activity and are co-administered with SSRIs to increase their antidepressant effects. The mechanism for this interaction may be an additional increase in the extracellular serotonin levels produced when SSRIs are provided with 5-HT2A antagonists. In addition, blockade of the 5-HT2A receptor is part of the pharmacological profile of antidepressant drugs such as myanserine and mirtazapine.

Serotonin receptor type 5-HT6 is almost exclusively localized in the central nervous system (CNS). Localization of 5-HT6 receptors in cerebral limbic and cortical brain regions, and relatively strong affinity and antagonism of some antipsychotics (clozapine, olanzapine, sertindol) and antidepressants (myan serine, amitriptyline) at the 5-HT6 receptor Both mechanism activity suggests a potential role in the pathophysiology and treatment of CNS disorders. Recent data in the literature indicate that blockade of 5-HT6 receptors results in an increase in cholinergic delivery, antidepressant activity, and antidepressant activity due to increased noradrenaline and dopamine functional delivery, and anti-anxiety. It can be associated with an effect. The 5-HT6 receptor has emerged as a very interesting molecular target, and its antagonists may act as potential drugs for the treatment of disorders characterized by cognitive disorders such as Alzheimer's disease, schizophrenia, depression and anxiety. Obvious (Liu K., Robichaud A., Drug Development Research 70,145-168, 2009; Wesołowska, A; Nikiforuk, A, Neuropharmacology 52 (5), 1274-83, 2007). In addition, 5-HT6 receptor antagonists have been shown to be effective in food intake and weight loss by clinically approved mechanisms consistent with improved satiety. Therefore, some compounds with 5-HT6 receptor antagonistic activity are currently clinically evaluated for the treatment of obesity (Heal D. et al., Pharmacology therapeutics, 117 (2), 207-231, 2008).

Intensive studies conducted since 1993 indicate that serotonin-functional 5-HT7 receptors may play a role in neuronal excitability as well as in the regulation of circadian rhythm, sleep, thermoregulation, cognitive processes, pain and migraine headaches. The strong affinity and antagonistic activity of some antipsychotic and antidepressant drugs at the 5-HT7 receptor suggests a potential role for these receptors in the pathophysiology of many neuropsychiatric disorders. In light of the behavioral data presented in the literature, it was established that selective 5-HT7 receptor antagonists produce antidepressant and anti-anxiety activity in rats and mice (Wesołowska A. et al., Neuropharmacology 51, 578-586, 2006). ). Using a mouse model of antipsychotic activity, Galici et al. Have shown that the selective 5-HT7 receptor antagonist SB-269970 can also induce antipsychotic-like effects (Galici R. et al., Behav. Pharmacol .; 19 (2), 153-9, 2008).

Serotonin-functional 5-HT2C and histamine-functional H1 receptors localized in the hypothalamus play an important role in regulating food intake. Blockade of these two types of receptors produced by antipsychotic drugs is most closely correlated with weight gain and increased risk of diabetes. On the other hand, blockade of 5-HT2C receptors, localized mostly in the cortical region and hippocampus, striatum, septum, thalamus and midbrain nucleus, can produce beneficial antidepressant and pro-cognitive effects. In medulla, 5-HT2C receptors are co-existing with GABA, indicating that they lead to indirect regulation of dopaminergic delivery. As a result, blockade of the 5-HT2C receptor along with blockade of the 5-HT2A receptor will potentiate the D2 receptor-mediated strain inhibition of dopaminergic projections with a protective effect against extrapyramidal symptoms (Kim D Et al., Neurotherapeutics, 6 (1), 78-85, 2009). The histamine H1 receptor blockade produced by antipsychotic drugs may be associated with clinically beneficial sedative effects in the regulation of arousal with acute phases of psychosis. Simultaneous degradation in the affinity of new molecules for these two types of receptors appears to be a protective factor against overweight. However, due to certain benefits of blockade of 5-HT2C and H1 receptors, the overall removal of affinity for these receptors may not be necessary.

Blockade of alpha2 adrenergic receptors enhances antidepressant-induced increases in extracellular monoamines. This suggests that substances that inhibit monoamine transporters and, at the same time, block alpha2 adrenergic receptors, can be potent and rapidly acting new antidepressants. In addition, alpha2 antagonists can enhance acetylcholine secretion and improve cognitive function in the frontal cortex, which can provide additional advantages in both antidepressant and antipsychotic therapies (particularly in negative symptoms). . Blockade of alpha2 adrenergic receptors may also respond to sexual dysfunction caused by serotonin reuptake inhibitors (Millan M., Neurotherapeutics, 6 (1), 53-77, 2009). Alpha2 antagonists may also be beneficial for the reduction of extrapyramidal symptoms caused by blockade of the D2 receptor in the striatum. Similarly, despite the potential peripheral side effects associated with hypotension, blockade of alpha1 adrenergic receptors can lead to some central nervous system benefits associated with the reduction of the risk of extrapyramidal side effects caused by antipsychotics. This may be related to the interaction between noradrenaline and serotonin neurons (Horacek J. et al., CNS Drugs, 20 (5), 389-409, 2006).

Sigma receptors are a separate group from CNS receptors; Their physiological role is still unknown. Some antipsychotic substances such as penciclidine, methamphetamine, heroin or dextrometropan are known to be potent sigma receptor agonists. On the other hand, haloperidol, a traditional antipsychotic drug, is a potent antagonist of sigma receptors, which may be important for antipsychotic potential. It has been established that selective sigma receptor agonists can produce antidepressant effects (Cobos E. et al., Curr. Neuropharmacol., 6 (4), 344-66, 2008). The findings provide evidence that sigma receptor affinity may contribute to the overall beneficial pharmacological profile of the novel psychotropic drug.

Because of the important role of cholinergic systems in the cognitive process, current research focuses on substances that can directly or indirectly enhance the activity of cholinergic systems. It includes substances that are agonists of selected subtypes of nicotinic or muscarinic receptors and antagonists of the 5-HT6 receptor. On the other hand, the potential precognitive effect caused by the interaction with the receptor can be masked by anticholinergic activity. Thus, substances free from the antagonistic properties of cholinergic receptors are within the scope of interest. This strategy also allows the elimination of many unwanted peripheral autonomic effects such as constipation, dry mouth or tachycardia (Miyamoto S. et al., Mol. Psychiatry; 10 (1), 79-104, 2005). In addition, M3 muscarinic receptors have been shown to be involved in the regulation of insulin secretion and their activation stimulates the pancreas to secrete insulin. Therefore, M3 receptor blockade can be expected to be undesirable in view of the risk of progression of type II diabetes in patients treated with second generation antipsychotics (eg olanzapine, clozapine, quetapin). Recent research has focused on substances that are free from these unwanted effects (Silvestre J.S., Prous J., Methods Find.Exp. Clin.Pharmacol .; 27 (5), 289-304, 2005).

Another serious side effect caused by antipsychotic drugs such as sertindol, ziprasidone is cardiac arrhythmias associated with delayed repolarization of cardiomyocytes. This condition is manifested as an extended and modified QT interval (QTc) on the electrocardiogram (ECG), which is most often caused by substances blocking hERG potassium channels. In order to prevent the introduction of pro-arrhythmic potential into pipeline drugs under development, at the very early stages of the study, new materials are screened in vitro for the efficacy of blocking hERG potassium channels using electrophysiological methods (Recanatini M Et al., Med. Res. Rev., 25 (2), 133-66, 2005).

Although the introduction of new psychotropic drugs (particularly neuroleptics, antidepressants, benzodiazepines, acetylcholinesterase inhibitors), the 50-thies of the XX century were unsuspecting breakthroughs, and thus neuropsychiatric disorders. The treatment of is still unsatisfactory because of both the limited efficacy and the broad spectrum of side effects caused by the available drugs. These drawbacks are a challenge in recent drug therapies, and there are ongoing efforts to find new, more effective psychotropic drugs.

Some indolepiperazine derivatives are known at the current state of the art.

WO 99/05140 describes indole and 2,3-dihydroindole derivatives having an antagonist activity on 5-HT1A serotonin-functional receptors and inhibiting serotonin reuptake.

WO 99/55672 describes hydroxyalkyl derivatives of alicyclic amines which exhibit antagonist activity on D2 dopamine functional receptors, and antagonist and agonist activity on 5-HT1A receptors.

WO2004 / 046124 relates to benzoxazinone derivatives having a high affinity for the 5-HT1 receptor and / or the ability to inhibit serotonin reuptake.

WO02 / 32863 describes indole derivatives having antagonist activity on the 5-HT6 receptor.

WO98 / 28293 describes several indoleamine derivatives having activity against D4 and 5-HT1A and / or 5-HT2A receptors and / or inhibition of serotonin reuptake.

EP900792A and WO97 / 36893 describe compounds with high affinity for D2 dopamine functional and 5-HT1A serotonin functional receptors.

WO96 / 03400 describes indolopiperazine derivatives which are potent agonists and antagonists of the 5-HT1 serotonin-functional receptor.

WO01 / 49680 describes aminoindole derivatives that bind strongly to the 5-HT1A receptor and are useful for the treatment of some psychiatric and neurological disorders.

WO02 / 36562 describes 1-aryl and 1-alkylsulfonyl heterocyclylbenzazoles as 5-HT6 receptor ligands.

It is an object of the present invention to provide novel compounds that are potentially useful for the treatment of central nervous system diseases. It is a further object of the present invention to provide novel compounds useful for the treatment of central nervous system diseases which have a higher effect than the agents currently used. It is yet another object of the present invention to provide novel compounds useful in the treatment of central nervous system diseases which can eliminate or minimize the adverse effects associated with the currently used therapies.

The present invention is a novel indolamine compound having a structure represented by the following general formula (IA),

And pharmaceutically acceptable salts thereof,

here

R ¹ is benzyl unsubstituted or substituted with a halogen atom, —OH, or C ₁ -C ₃ -alkyl; Or phenylsulfonyl unsubstituted or substituted with a halogen atom, -OH or C ₁ -C ₃ -alkyl in the phenyl ring;

G ¹ represents a piperazine moiety of the formula

here

n is 3 or 4,

m is 1,

A ¹ is phenyl unsubstituted or substituted with one substituent selected from the group consisting of a halogen atom, -OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl;

A moiety selected from the group consisting of 3,4-dihydroquinolin-2 ( 1H ) -one-yl, 1,4-benzodioxanyl and benzofuranyl, the moiety being linked via a carbon atom of the benzene ring tea; or

Imidazolidin-2-one-yl linked via that nitrogen atom;

.

One group of compounds of the invention is a compound of formula (IA), wherein A ¹ is unsubstituted or substituted with one substituent selected from the group consisting of halogen atoms, -OH, C ₁ -C ₃ -alkyloxy, and phenyl Phenyl; A moiety selected from the group consisting of 3,4-dihydroquinolin-2 ( 1H ) -one-yl, 1,4-benzodioxanyl and benzofuranyl, the moiety being linked via a carbon atom of the benzene ring tea; Or imidazolidin-2-one-yl linked via the nitrogen atom; R ¹ , n, m have the meaning as defined above for formula (IA).

Another group of compounds of the present invention are compounds of formula (IA), wherein A ¹ is substituted with one substituent selected from the group consisting of halogen atoms, -OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl Or unsubstituted phenyl; A moiety selected from the group consisting of 3,4-dihydroquinolin-2 ( 1H ) -one-yl, 1,4-benzodioxanyl and benzofuranyl, the moiety being linked via a carbon atom of the benzene ring T; and R ¹ , n, m have the meaning as defined above for Formula (IA).

A further group of compounds of the invention is a compound of formula (IA), wherein A ¹ represents 3,4-dihydroquinolin-2 (1 H ) -one-yl. Preferably, A ¹ in this group represents 3,4-dihydroquinolin-2 ( 1H ) -one-7-yl.

Another group of compounds of the invention is a compound of formula (IA), wherein A ¹ represents unsubstituted phenyl.

Another group of compounds of the invention is a compound of formula (IA), wherein A ¹ is a substituent selected from the group consisting of halogen atoms, -OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl Substituted phenyl. Preferably, the substituents are selected from the group consisting of halogen atoms, C ₁ -C ₃ -alkyloxy and -CONH ₂ .

A further group of compounds of the present invention are compounds of formula (IA), wherein R ¹ represents unsubstituted phenylsulfonyl.

Another additional group of compounds of the invention is a compound of formula (IA), wherein R ¹ represents unsubstituted benzyl.

Another group of compounds of the invention are compounds of formula (IA), wherein R ¹ represents benzyl substituted with halogen atoms, preferably benzyl substituted with fluorine or chlorine.

Preferred sub-groups of the compounds of the invention are compounds of formula (IA), wherein A ¹ represents 3,4-dihydroquinolin-2 (1 H ) -one-yl and R ¹ is unsubstituted phenylsul Ponyl.

Another additional sub-group of the compounds of the invention is a compound of formula (IA), wherein A ¹ represents 3,4-dihydroquinolin-2 (1 H ) -one-yl and R ¹ is substituted with a halogen atom Benzyl, preferably substituted with fluorine or chlorine.

Preferred sub-groups of the compounds of the invention are compounds of formula (IA), wherein A ¹ represents unsubstituted phenyl and R ¹ represents unsubstituted phenylsulfonyl.

Another sub-group of compounds of the invention is a compound of formula (IA), wherein A ¹ represents unsubstituted phenyl and R ¹ represents unsubstituted benzyl.

Another further sub-group of compounds of the invention is a compound of formula (IA) wherein A ¹ represents unsubstituted phenyl and R ¹ represents benzyl substituted with a halogen atom, preferably fluorine or chlorine Indicates.

Preferred sub-groups of the compounds of the invention are compounds of formula (IA), wherein A ¹ is in the group consisting of halogen atoms, —OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl, preferably Phenyl substituted with one substituent selected from the group consisting of halogen atom, C ₁ -C ₃ -alkyloxy and -CONH ₂ , R ¹ represents unsubstituted phenylsulfonyl.

Another sub-group of the compounds of the invention is a compound of formula (IA), wherein A ¹ is in the group consisting of halogen atoms, —OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl, preferably Phenyl substituted with one substituent selected from the group consisting of halogen atom, C ₁ -C ₃ -alkyloxy and -CONH ₂ , R ¹ represents unsubstituted benzyl.

Another further sub-group of compounds of the invention is a compound of formula (IA), wherein A ¹ is preferred in the group consisting of halogen atoms, —OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl Preferably phenyl substituted with one substituent selected from the group consisting of halogen atoms, C ₁ -C ₃ -alkyloxy and -CONH ₂ , R ¹ is benzyl substituted with a halogen atom, preferably substituted with fluorine or chlorine Indicates.

Reference may be made to the following specific compounds of formula (IA) of the invention:

7- [3- [4- (1-benzylindol-4-yl) piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one

7- (4- (4- (1-benzyl-1 H -indol-4-yl) piperazin-1-yl) butoxy) -3,4-dihydroquinolin-2 (1H) -one

7- [3- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H-quinoline- 2-on

7- [3- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H-quinoline- 2-on

7- [3- [4- [1-[(3-hydroxyphenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H-quinoline- 2-on

7- [3- [4- [1- (m-tolylmethyl) indol-4-yl] piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one

4- (4- (3-phenoxypropyl) piperazin-1-yl) -1- (phenylsulfonyl) -1 H -indole

4- (4- (3- (4-fluorophenoxy) propyl) piperazin-1-yl) -1- (phenylsulfonyl) -1H-indole

(4- (3- (2- (1-methylethoxy) phenoxy) propyl) piperazin-1-yl) -1- (phenyl-sulfonyl) -1 H -indole

7- [3- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one

7- (4- (4- (1- (phenylsulfonyl) -1 H -indol-4-yl) piperazin-1-yl) butoxy) -3,4-dihydroquinoline-2 (1H)- On

4- (4- (3- (benzofuran-6-yloxy) propyl) piperazin-1-yl) -1- (phenylsulfonyl) -1 H -indole

2- [3- [4- (1-benzylindol-4-yl) piperazin-1-yl] propoxy] benzamide

7- [4- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2 -On

2- [3- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

7- [4- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2 -On

2- [3- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

7- [4- [4- [1-[(4-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2 -On

2- [3- [4- [1-[(4-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

7- [4- [4- [1-[(3-chlorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2- On

2- [3- [4- [1-[(3-chlorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

1- (benzenesulfonyl) -4- [4- (4-phenoxybutyl) piperazin-1-yl] indole

1- (benzenesulfonyl) -4- [4- [4- (4-fluorophenoxy) butyl] piperazin-1-yl] -indole

1- (benzenesulfonyl) -4- [4- [4- (2-isopropoxyphenoxy) butyl] -piperazin-1-yl] indole

2- [3- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] propoxy] -benzamide

2- [4- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] butoxy] -benzamide

And pharmaceutically acceptable salts and solvates thereof.

The indoleamine derivatives of the above formula (IA) are preferably dopaminergic, in particular D2 and D3, serotonin-functional, in particular 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and adrenergic, in particular α1 and α2C As shown, affinity for a receptor recognized as a therapeutic target in the treatment of CNS disorders. In addition, the compounds of formula (IA) exhibit affinity for serotonin transporters (SERT, 5-HTT), with potassium channel hERG, muscarinic receptor M3, histamine functional receptor H1 or serotonin functional receptor 5-HT2C. Likewise, they have low affinity for biological targets associated with adverse reactions. Thanks to such a broad pharmacological profile, the compounds of the present invention are not related and unrelated to taking central nervous system disorders such as schizophrenia, schizophrenia disorder, schizophrenic disorder, delusion syndrome and psychoactive substances. Psychotic conditions, emotional disorders, depression, emotional bipolar disorder, manic episodes, anxiety disorders of various etiologies, consciousness disorders including lethargy, alcoholic or other etiologies delirium, aggressiveness, psychomotor and other behavioral disorders, sleep of various etiologies Disorders, withdrawal syndrome of various etiologies, addiction, pain syndrome of various etiologies, poisoning with psychoactive substances, disorders of the brain circulation of various etiologies, mental retardation disorders of various etiologies, transition disorders, dissociation disorders, urination disorders, autism and nocturnal enuresis , Stuttering, other developmental disorders including ticks, various types of cognitive disorders such as Alzheimer's disease, central And medicaments as medicaments for the treatment and / or prevention of psychopathological symptoms and neurological disorders in the course of other diseases of the peripheral nervous system.

Accordingly, the subject of the present invention is a compound of formula (IA) as defined above for use as a medicament.

In the treatment of central nervous system disorders the compounds of formula (IA) may be administered in the form of pharmaceutical compositions or preparations containing them.

Accordingly, the subject of the invention is also a pharmaceutical composition containing a compound as defined above or a compound of formula (IA) as the active substance, in combination with a pharmaceutically acceptable carrier (s) and / or excipients.

Subjects of the present invention are also the use of indole derivatives of formula (IA) above for the treatment of disorders of the central nervous system.

The present invention also relates to a mammal comprising a human comprising administering a therapeutically effective amount of a compound of formula (IA) or a pharmaceutical composition containing a compound of formula (IA) as defined above as an active substance. It relates to a method of treating central nervous system disorders.

The terms used in the detailed description of the present invention have the following meanings.

The term “C ₁ -C ₃ -alkyl” relates to a saturated, straight or branched hydrocarbon group having the indicated number of carbon atoms. Specific examples of groups included in this term are methyl, ethyl, n-propyl, isopropyl.

The term "halogen atom" relates to a substituent selected from F, Cl, Br and I.

The term “C ₁ -C ₃ -alkyloxy” relates to an —OC ₁ -C ₃ -alkyl group wherein C ₁ -C ₃ -alkyl refers to a saturated, straight or branched hydrocarbon group having the indicated number of carbon atoms. It is about. Specific examples of groups included in these terms are methoxy, ethoxy, n-propoxy, isopropoxy.

Compounds of formula (IA) according to the invention can be prepared by the process shown in the following scheme.

Suitable secondary amines of formula (IIA) or acid addition salts thereof, preferably hydrochloride, are prepared in the presence of excess base, for example triethylamine or potassium carbonate, in the presence of a catalytic amount of potassium iodide, optionally at elevated temperatures. , An N-alkylation reaction with an appropriate halogen derivative of formula (III) gave a compound of formula (IA) of the present invention. The reaction was carried out, for example, at 70 ° C. in acetonitrile. The reaction time was typically 8 to 12 hours.

Starting secondary amines of formula ( IA ) can be prepared by methods known in the art. Amines of formula ( IIA ) as hydrochlorides can be obtained by the method shown in the following scheme.

Commercially available 4- (4-Boc-piperazin-1-yl) -1H-indole is prepared in the presence of a base, for example potassium tert-butoxide, and in the presence of a crown ether catalyst. A nucleophilic substitution reaction is performed with the halogen derivative. The reaction is initially carried out at low temperature, for example at 0 ° C., and then at ambient temperature in anhydrous tetrahydrofuran as solvent. The reaction time is usually 10 to 14 hours.

The amine Boc- (IIA), the product of the substitution reaction, was deprotected using a 4M solution of hydrogen chloride in dioxane, and the resulting amine, as the hydrochloride, was followed by the synthesis of the compound of formula (IA) of the present invention. Used without further purification in the step.

Halogen derivatives of formula (IV) are known and commercially available.

Halogen derivatives of formula (III) are well known or commercially available or can be prepared from commercially available starting materials by adjusting and applying known methods.

The preparation of exemplary compounds of formula (IA) and starting materials of formula (IIA) is described in detail in the experimental section.

Since the compounds of formula (IA) have alkaline characteristics (containing one or more tertiary amine groups), they can form acid addition salts.

Salts with acids may be pharmaceutically acceptable, especially if they are intended to be the active ingredient in pharmaceutical compositions. The invention also relates to salts of compounds of formula (IA) with acids other than pharmaceutically acceptable ones, which may be useful, for example, as suitable intermediates for the purification of the compounds of the invention. Indeed, in order to purify the compound, the compound is first separated from the reaction mixture in the form of a pharmaceutically unacceptable salt, and then converted to the free base by treatment of the salt with an alkali agent, followed by separation and optionally back to the salt. Is often preferred.

Acid addition salts may be formed with inorganic (mineral) acids or organic acids. In particular, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, carbonic acid, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, p-toluene Sulphonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid such as 2-naphthalene-sulfonic acid, pamoic acid, thinnapoic acid or hexanoic acid may be mentioned as examples of acids.

The acid addition salts may be reacted in a simple manner by reacting the compound of formula (I) with a suitable inorganic or organic acid, optionally in a suitable solvent, such as an organic solvent, to form a salt that is usually separated by, for example, crystallization and filtration. It can be prepared as. For example, a compound in free base form may be prepared by reacting a compound in solution, such as methanol, with a stoichiometric amount of hydrochloric acid or a solution of hydrochloric acid in methanol, ethanol or diethyl ether, followed by evaporation of the solvent (s). Can be converted into the corresponding hydrochloride salt.

The term “disorders of the central nervous system” refers to schizophrenia, schizophrenia disorders, schizophrenic disorders, delusional syndromes and other psychotic conditions associated with and not related to taking psychoactive substances, emotional disorders, bipolar disorders, mania, depression , Anxiety disorders of various etiologies, stress reactions, consciousness disorders, lethargy, alcoholic or other etiologies, aggression, psychomotor irritability and other behavioral disorders, sleep disorders of various etiologies, withdrawal syndrome of various etiologies, addiction, pain of various etiologies Syndrome, addiction to psychoactive substances, brain circulation disorders of various etiologies, mental and physical disorders of various etiologies, transition disorders, dissociation disorders, urination disorders, autism and nocturnal enuresis, stuttering, and other developmental disorders, including ticks Psychopathological symptoms and neurological in the course of cognitive impairment of, eg, Alzheimer's disease, other diseases of the central and peripheral nervous system It should be understood to include disorders selected from the cliff.

In the treatment of the aforementioned disorders, the compounds of formula (IA) of the present invention may be administered as chemical compounds, but are usually present as active ingredients in combination with pharmaceutically acceptable carrier (s) and / or excipient (s). It will be applied in the form of a pharmaceutical composition containing a compound of the invention or a pharmaceutically acceptable salt thereof as described above.

In the treatment of the aforementioned disorders, the pharmaceutical compositions of the invention can be delivered by any route of administration, preferably orally or parenterally, and depending on the intended route of administration, Will have a form.

Compositions for oral administration may take the form of solid or liquid preparations. Solid formulations include, for example, pharmaceutically acceptable inactive ingredients such as binding agents (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); Fillers (eg lactose, sucrose, carboxy methylcellulose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (eg magnesium stearate, talc or silica); Disintegrants (eg crospovidone, corn starch or sodium starch glycolate); It may be in the form of tablets or capsules, prepared in a conventional manner using wetting agents (eg sodium lauryl sulfate). Tablets may be coated with conventional coatings, delayed / controlled release coatings or enteric coatings using methods well known to those skilled in the art. Liquid formulations for oral administration may, for example, be in the form of solutions, syrups or suspensions, or may be prepared on the fly from dry products suitable for recombination with water or other suitable carriers. Such liquid formulations include pharmaceutically acceptable inert ingredients such as suspension agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (eg lecithin or acacia gum), non-aqueous matrix components (eg Almond oil, oil esters, ethyl alcohol or fractionated vegetable oils) and preservatives (eg methyl or propyl p-hydroxybenzoate or sorbic acid), for example. The formulations may also contain suitable buffering systems, flavoring and fragrances, colorants and sweeteners.

Formulations for oral administration can be formulated according to methods well known to those skilled in the art to provide controlled release of the active compound.

Routes for parenteral administration include administration by intramuscular and intravenous injection and continuous intravenous infusion. Compositions for parenteral administration may, for example, be in multidose containers with the addition of ampoules in unit dosage form or with a preservative. The compositions may be in the form of emulsions, suspensions or solutions in oils or aqueous media, and may contain pharmaceutically acceptable excipients such as suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient may be in the form of a powder for instant reconstitution in a suitable carrier, eg, sterile pyrogen-free water.

The method of treatment with a compound of the invention will be based on administering a therapeutically effective amount of a compound of the invention to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.

Suggested dosages of the compounds of the invention will include a range of 1 to about 1000 mg per day, in single or divided doses. It will be apparent to those skilled in the art that the choice of dosage required to achieve the desired biological effect will depend on several factors, such as the type of specific compound, the indication, the route of administration, the age and the condition of the patient, and the precise administration. The amount will be determined at the discretion of the attending physician.

Example  One.

Preparation of Starting Amines of Formula (IIA) and Halogen Derivatives of Formula (III)

General procedure for the preparation of amines of formula (IIA)

To a solution of potassium tert-butoxide (2.16 ml of 1M solution in tetrahydrofuran, 1.3 eq.) In 7 ml of dry tetrahydrofuran and crown ether 18-crown-6 (0.2 eq.), 10 ml of dry tetrahydro A solution of 4-tert-butyl (1H-indol-4-yl) -piperazine-1-carboxylate ( Boc -P ) (1.66 mmol, 1 eq.) In furan was added dropwise at 0 ° C. After 20 minutes halogen derivative (IV) (2.49 mmol, 1.5 eq.) Was added and the resulting suspension was stirred overnight at ambient temperature. Tetrahydrofuran was then evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was extracted with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated and the crude reaction mixture was purified by column chromatography using solvent system hexane / ethyl acetate 8: 2 to give solid product Boc- (IIA). The yield of Boc- (IIA) is in the range of 85-95%.

Compound Boc- (IIA) was deprotected according to the following procedure.

A mixture of amine Boc- (IIA) (0.589 mmol) and 4M hydrogen chloride solution in dioxane (3 ml) was stirred at room temperature for 20 minutes, and then the solvent was evaporated under reduced pressure. Deprotected amine (IIA) as a hydrochloride was obtained in 95% yield and used without further purification in the next step of the synthesis of the compound of formula (IA) of the present invention.

According to the above procedure, the following amines of formula ( IA ) were prepared:

1-benzyl-4-piperazin-1-yl-1H-indole ( IA- 1 ) as hydrochloride was prepared from Boc-P and benzyl bromide, MS: 292 [M + H ⁺ ],

1- (2-fluorobenzyl) -4-piperazin-1-yl-1H-indole ( IA- 2 ) as hydrochloride was prepared from Boc-P and 2-fluorobenzyl bromide, MS: 310 [M + H ⁺ ],

1- (3-fluorobenzyl) -4-piperazin-1-yl-1H-indole ( IIA -3 ) as hydrochloride was prepared from Boc-P and 3-fluorobenzyl bromide, MS: 310 [M + H ⁺ ],

3-[(4-piperazin-1-yl-1 H -indol-1-yl) methyl] phenol ( IIA- 4 ) as hydrochloride was prepared from Boc-P and 3- (bromomethyl) phenol, MS : 308 [M + H ⁺ ],

1- (3-methylbenzyl) -4-piperazin-1-yl-1H-indole ( IA- 5 ) as hydrochloride was prepared from Boc-P and 1- (bromomethyl) -3-methylbenzene, MS : 306 [M + H ⁺ ],

1- (phenylsulfonyl) -4-piperazin-1-yl-1H-indole ( IIA- 6 ) as hydrochloride was prepared from Boc-P and benzenesulfonyl chloride, MS: 342 [M + H ⁺ ],

1-[(2-fluorophenyl) sulfonyl] -4-piperazin-1-yl-1H-indole ( IA- 7 ) as hydrochloride was prepared from Boc-P and 2-fluorobenzenesulfonyl chloride, MS: 360 [M + H ⁺ ],

1-[(3-fluorophenyl) sulfonyl] -4-piperazin-1-yl-1H-indole ( IIA -8 ) as hydrochloride was prepared from Boc-P and 3-fluorobenzenesulfonyl chloride, MS: 360 [M + H ⁺ ],

Hydrochloride as a 1 - [(4-fluorophenyl) sulfonyl] was prepared from 4-piperazin-1-yl -1H- indole-benzenesulfonyl chloride a (IIA -9) with Boc-P and 4-fluoro, MS: 360 [M + H ⁺ ],

3-[(4-piperazin-1-yl-1 H -indol-1-yl) sulfonyl] phenol ( IIA- 10 ) as hydrochloride was prepared from Boc-P and 3-hydroxybenzenesulfonyl chloride, MS: 358 [M + H ⁺ ],

1-[(3-methylphenyl) sulfonyl] -4-piperazin-1-yl-1H-indole ( IIA -11 ) as hydrochloride was prepared from Boc-P and 3-methylbenzenesulfonyl chloride, MS: 356 [M + H ⁺ ],

1- (4-fluorobenzyl) -4-piperazin-1-yl-1H-indole ( IIA- 16 ) as hydrochloride was prepared from Boc-P and 4-fluorobenzyl bromide, MS: 310 [M + H ⁺ ],

1- (3-chlorobenzyl) -4-piperazin-1-yl-1H-indole ( IA- 17 ) as hydrochloride was prepared from Boc-P and 3-chlorobenzyl bromide, MS: 326 [M + H ⁺ ],

Halogen derivatives ( III ) are commercially available (if marked with an asterisk *) or can be obtained by methods known and described in the literature.

(3-bromopropoxy) benzene ( III -2 ) *,

1- (3-bromopropoxy) -4-fluorobenzene ( III -5 ) *,

1- (3-Chloropropoxy) -2- (1-methylethoxy) benzene ( III- 11 ) by Walsh, David A. et al., Journal of Medicinal Chemistry , 32 (1), 105-18; Prepared according to the method described in 1989.

7- (3-bromopropoxy) -3,4-dihydroquinolin-2 ( 1H ) -one ( III- 20 ) was prepared by Banno, Kazuo et al., Chemical & Pharmaceutical Bulletin, 1988, 36 (11), 4377 Prepared according to the method described in -88.

7- (4-Bromobutoxy) -3,4-dihydroquinolin-2 ( 1H ) -one ( III- 21 ) was prepared according to the method described in US2008 / 0293736.

6- (3-chloropropoxy) -1 H -indole ( III- 22 ) *,

6- (3-chloropropoxy) -1-benzofuran ( III- 23 ) *,

(4-bromobutoxy) benzene ( III- 27 ) *,

1- (4-bromobutoxy) -4-fluorobenzene ( III -28 ) *,

1- (4-chlorobutoxy) -2- (1-methylethoxy) benzene ( III- 29 ) by Walsh, David A. et al., Journal of Medicinal Chemistry , 32 (1), 105-18; Prepared according to the method described in 1989.

2- (3-Chloropropoxy) benzamide ( III- 30 ) was prepared according to the method described in Kowalski, P., J. Heterocyclic Chem., 48, 192-198, 2011.

2- (4-Chlorobutoxy) benzamide ( III- 31 ) was prepared according to the methods described in Kowalski, P., J. Heterocyclic Chem., 48, 192-198, 2011.

Example  2.

Process of preparation of compound (IA) according to the invention

a1 ) amine (IIA) hydrochloride (0.354 mmol, 1.0 eq. ) in 7 ml acetonitrile, halogen derivatives of formula (III) (0.425 mmol, 1.2 eq.), triethylamine (0.788 mmol, 2.2 eq.) and iodide The mixture of potassium (0.2 eq.) Was stirred at 70 ° C. for 8 hours. The solvent was then evaporated and the residue was purified by column chromatography in solvent system methylene chloride / methanol 95: 5 v / v to give compounds of formula (IA) according to the invention in yields ranging from 70-90%. .

a2 ) amine (IIA) hydrochloride (0.520 mmol, 1.2 eq. ) in 10 ml acetonitrile, halogen derivative of formula (III) (0.430 mmol, 1.0 eq.), potassium carbonate (1.29 mmol, 3 eq.) and potassium iodide (0.2 eq.) Was stirred at 70 ° C. for 12 h. The inorganic precipitate is then filtered off, the solvent is evaporated from the filtrate and the residue is purified by column chromatography in a solvent system methylene chloride / methanol 95: 5 v / v to give a compound of formula (IA) according to the invention Obtained in yields in the range of 70-90%.

According to one of the above procedures a1 and a2 , a compound of formula (IA) was prepared according to the invention.

Compound 4. 7- [3- [4- (1-benzylindol-4-yl) piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one

According to procedure a1) the title compound was prepared using amine (IIA-1) and halogen derivative (III-20) as starting materials.

Compound 5. 7- (4- (4- (1-benzyl-1 H -indol-4-yl) piperazin-1-yl) butoxy) -3,4-dihydroquinolin-2 (1H) -one

According to procedure a1) the title compound was prepared using amine (IIA-1) and halogen derivative (III-21) as starting materials.

Compound 6. 7- [3- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H -Quinolin-2-one

The title compound was prepared according to procedure a1) using amine (IIA-2) and halogen derivative (III-20) as starting materials. MS: 513 [M + H ⁺ ]

Compound 8. 7- [3- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H -Quinolin-2-one

The title compound was prepared according to procedure a1) using amine (IIA-3) and halogen derivative (III-20) as starting materials. MS: 513 [M + H ⁺ ]

Compound 9. 7- [3- [4- [1-[(3-hydroxyphenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H -Quinolin-2-one

The title compound was prepared according to procedure a1) using amine (IIA-4) and halogen derivative (III-20) as starting materials. MS: 511 [M + H ⁺ ]

Compound 10. 7- [3- [4- [1- (m-tolylmethyl) indol-4-yl] piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinoline-2- On

The title compound was prepared according to procedure a1) using amine (IIA-5) and halogen derivative (III-20) as starting materials. MS: 509 [M + H ⁺ ]

Compound 12. 4- (4- (3-phenoxypropyl) piperazin-1-yl) -1- (phenylsulfonyl) -1 H -indole

The title compound was prepared according to procedure a2) using amine (IIA-6) and halogen derivative (III-2) as starting materials.

Compound 15. 4- (4- (3- (4-fluorophenoxy) propyl) piperazin-1-yl) -1- (phenylsulfonyl) -1H-indole

According to procedure a2) the title compound was prepared using amine (IIA-6) and halogen derivative (III-5) as starting materials.

Compound 21. 4- (4- (3- (2- (1-methylethoxy) phenoxy) propyl) piperazin-1-yl) -1- (phenyl-sulfonyl) -1 H -indole

According to procedure a2) the title compound was prepared using amine (IIA-6) and halogen derivative (III-11) as starting materials.

Compound 23. 7- [3- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one

According to procedure a1) the title compound was prepared using amine (IIA-1) and halogen derivative (III-20) as starting materials.

Compound 24. 7- (4- (4- (1- (phenylsulfonyl) -1 H -indol-4-yl) piperazin-1-yl) butoxy) -3,4-dihydroquinoline-2 ( 1H) -on

According to procedure a1) the title compound was prepared using amine (IIA-6) and halogen derivative (III-21) as starting materials.

Compound 25. 4- (4- (3- (benzofuran-6-yloxy) propyl) piperazin-1-yl) -1- (phenyl-sulfonyl) -1 H -indole

According to procedure a2) the title compound was prepared using amine (IIA-6) and halogen derivative (III-23) as starting materials.

Compound 60. 2- [3- [4- (1-benzylindol-4-yl) piperazin-1-yl] propoxy] benzamide

According to procedure a1) the title compound was prepared using amine (IIA-1) and halogen derivative (III-30) as starting materials.

Compound 61. 7- [4- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H- Quinolin-2-one

The title compound was prepared according to procedure a1) using amine (IIA-2) and halogen derivative (III-21) as starting materials.

Compound 62. 2- [3- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

The title compound was prepared according to procedure a1) using amine (IIA-2) and halogen derivative (III-30) as starting materials.

Compound 63. 7- [4- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H- Quinolin-2-one

According to procedure a1) the title compound was prepared using amine (IIA-3) and halogen derivative (III-21) as starting materials.

Compound 64. 2- [3- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

The title compound was prepared according to procedure a1) using amine (IIA-3) and halogen derivative (III-30) as starting materials.

Compound 65. 7- [4- [4- [1-[(4-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H- Quinolin-2-one

According to procedure a1) the title compound was prepared using amine (IIA-16) and halogen derivative (III-21) as starting materials.

Compound 66. 2- [3- [4- [1-[(4-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

According to procedure a1) the title compound was prepared using amine (IIA-16) and halogen derivative (III-30) as starting materials.

Compound 67. 7- [4- [4- [1-[(3-chlorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline 2-on

According to procedure a1) the title compound was prepared using amine (IIA-17) and halogen derivative (III-21) as starting materials.

Compound 68. 2- [3- [4- [1-[(3-chlorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide

According to procedure a1) the title compound was prepared using amine (IIA-17) and halogen derivative (III-30) as starting materials.

Compound 69. 1- (benzenesulfonyl) -4- [4- (4-phenoxybutyl) piperazin-1-yl] indole

According to procedure a2) the title compound was prepared using amine (IIA-6) and halogen derivative (III-27) as starting materials.

Compound 70. 1- (benzenesulfonyl) -4- [4- [4- (4-fluorophenoxy) butyl] piperazin-1-yl] -indole

According to procedure a2) the title compound was prepared using amine (IIA-6) and halogen derivative (III-28) as starting materials.

Compound 71. 1- (benzenesulfonyl) -4- [4- [4- (2-isopropoxyphenoxy) butyl] -piperazin-1-yl] indole

According to procedure a2) the title compound was prepared using amine (IIA-6) and halogen derivative (III-29) as starting materials.

Compound 72. 2- [3- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] propoxy] -benzamide

The title compound was prepared according to procedure a1) using amine (IIA-6) and halogen derivative (III-30) as starting materials.

Compound 73. 2- [4- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] butoxy] -benzamide

According to procedure a1) the title compound was prepared using amine (IIA-6) and halogen derivative (III-31) as starting materials.

Example  3.

In Vitro Pharmacology: Binding Analysis

The affinity of the compounds of the invention for dopamine-, serotonin-, adrenergic, muscarinic M3, histamine-functional H1, sigma and serotonin transporter SERT receptors is determined using radioreceptor methods for these receptors. By measuring the binding, it was tested using the same method as described later. In addition, the compounds of the present invention were tested for their ability to block potassium channel hERG.

Specific ligand binding to a receptor is defined as the difference between total binding and non-specific binding measured in the presence of excess unlabeled ligand.

The result is the percentage of control specific binding obtained in the presence of the test compound ((measured specific binding / control specific binding) x 100), and the percentage of inhibition of control specific binding (100-((measured specific binding) / Control specific binding) x 100)). Specific ligand binding to a receptor is defined as the difference between total binding and nonspecific binding measured in the presence of excess unlabeled ligand. Scintillation counting was a method of detecting ligand binding. IC50 values (concentrations that cause half of the maximum inhibition of control specific binding) are Hill equation curve fitting (Y = D + [(A−D) / (1+ (C / C50) nH)], where Y = specific Non-linear regression analysis of competition curves generated with mean replicates using red binding, D = minimum specific binding, A = maximum specific binding, C = compound concentration, C50 = IC50, and nH = slope factor) Measured by This analysis was performed using software developed by Cerep (Hill Software) and validated against data generated by the commercial software SigmaPlot ^® 4.0 for Windows ^® (© 1997 by SPSS Inc.). Inhibition constant (Ki) is calculated using Cheng Prusoff equation (Ki = IC50 / (1+ (L / KD)), where L = concentration of radioligand in the assay, and KD = affinity of radioligand for receptor It was. Kd was measured using a scatter plot.

Conditions and methodology for in vitro testing are provided by reference to the literature.

Dopamine functional receptors D2  And D3 Affinity for

Experimental conditions for the tests are provided in Table 1, and test results for representative compounds are provided in Tables 2a and 2b (receptors D2 and D3) and Table 3 (receptor D4).

[Table 2a]

[Table 2a]

Serotonin functional receptor 5- HT1A , 5- HT2A , 5- HT6 , 5- HT7  And 5- HT2C Affinity for

The experimental conditions for the test are provided in Table 4, and the test results for representative compounds of the present invention are shown in Tables 5a and 5b (receptors 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7) and Tables 6a and 6b ( Receptor 5-HT2C).

methodology:

5-HT1A: Borsini et al. (1995), Naunyn. Sch. Arch. Pharmacol. 352: 276-282

5-HT2A: Bryan L. Roth. Assay Protocol Book. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. 2008.08.31 online: available at http://pdsp.med.unc.edu/UNC-CH%20Protocol%20Book.pdf

5-HT2C: Stam et al. (1994), Eur. J. Pharmacol., 269: 339-348

5-HT6: Bryan L. Roth. Assay Protocol Book. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. 2008.08.31 online: available at http://pdsp.med.unc.edu/UNC-CH%20Protocol%20Book.pdf

5-HT7: Bryan L. Roth. Assay Protocol Book. University of North Carolina At Chapel Hill. National Institute of Mental Health. Psychoactive Drug Screening Program. 2008.08.31 online: available at http://pdsp.med.unc.edu/UNC-CH%20Protocol%20Book.pdf

[Table 5a]

[Table 5b]

[Table 6a]

[Table 6b]

Affinity to adrenergic α1 and α2C receptors

Experimental conditions for the test are provided in Table 7, and test results for representative compounds are provided in Tables 8a and 8b (α1 receptor) and Tables 9a and 9b (α2C receptor).

[Table 8a]

[Table 8b]

[Table 9a]

[Table 9b]

Muskarine Castle  Affinity for receptors

Experimental conditions for the tests are provided in Table 10, and test results for representative compounds are provided in Table 11.

Serotonin Vehicle  ( SERT Affinity for) receptors

Experimental conditions for the tests are provided in Table 12, and test results for representative compounds are provided in Table 13.

H1 Histamine functionality  And affinity for σ receptor

Experimental conditions for the tests are provided in Table 14, and test results for representative compounds are provided in Tables 15A and 15B.

[Table 15a]

[Table 15b]

hERG  Ability to block potassium channels

The ability to block hERG potassium channels was measured using cloned hERG potassium channels (KCNH2 gene, expressed in CHO cells) and electrophysiological methods as biological materials. The effects were evaluated using the IonWorks Quattro system (MDS-AT).

A hERG current was derived using a pulse pattern with a fixed amplitude (conditioning pre-pulse: -80 mV for 25 ms; test pulse: +40 mV for 80 ms) from a holding potential of 0 mV. The hERG current was measured as the difference between the peak current at 1 ms after the test step up to +40 mV and the steady-state current at the end of the step up to +40 mV.

Data Analysis

Data acquisition and analysis was performed using IonWorks QuattroTM system operating software (version 2.0.2; Molecular Devices Corporation, Union City, CA). Data was corrected for leakage current. The hERG block is:

% Block = (1-ITA / IControl) x 100%

Where IControl and ITA were the currents drawn by the test pulses in the control and in the presence of test compounds, respectively.

Concentration-response data for blocking are consistent with the following form of equation:

% Blocking =% VC + {(% PC-% VC)-(% PC-% VC) / [1 + ([test] / IC50) N]},

Where [test] is the concentration of the test compound, IC50 is the concentration of the test compound causing half of the maximum inhibition, N is the Hill coefficient,% VC is the percentage of current discharge (mean current inhibition in the vehicle control),% PC Is the average inhibition of current to the positive control (1 μM E-4031), and% blocking is the percentage of ion channel current inhibited at each concentration of test compound. Nonlinear least squares was solved with the XLfit add-in for Excel 2003 (Microsoft, Redmond, WA).

Test results for each compound are shown in Tables 16a and 16b.

[Table 16a]

[Table 16b]

The in vitro test results presented above show that the compounds of the present invention show high affinity for the D3, 5-HT1A and 5-HT2A receptors, as well as for D2 and 5-HT6. This confirms their potential usefulness in the treatment of disorders associated with dopamine, serotonin and noradrenergic delivery, such as psychosis, depression as well as anxiety disorders. It should be emphasized that some of the compounds simultaneously possess high affinity for the D2 and 5-HT6 receptors. Such pharmacological profiles suggest possible efficacy in the treatment of antidepressant, precognitive and mood stabilizing activity as well as psychosis. At the same time, the compounds of the present invention possess weak affinity for hERG potassium channel and M3 muscarinic receptors and moderate affinity for H1 and 5-HT2C receptors. This can potentially contribute to the lowering of side effects such as deep vein, disorders of vegetative human condition, excessive appetite or metabolic disorders, which can be caused by drugs currently used in the treatment of the disease.

The in vitro test results presented above show that the compounds of the present invention exhibit high affinity for the D2, D3, 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, alpha1 and alpha2c receptors. . This confirms their potential usefulness in the treatment of disorders associated with dopamine, serotonin and noradrenergic delivery, such as psychosis, depression as well as anxiety disorders. It should be emphasized that some of the compounds simultaneously possess high affinity for the D2, D3, and 5-HT1A and / or 5-HT6 receptors, as well as the SERT receptor. Such pharmacological profiles suggest possible efficacy in the treatment of antidepressant, precognitive and mood stabilizing activity as well as psychosis. At the same time, the compounds of the present invention possess weak affinity for hERG potassium channel and M3 muscarinic receptors and moderate affinity for H1 and 5-HT2C receptors. This can potentially contribute to the lowering of side effects such as deep vein, disorders of vegetative human condition, excessive appetite or metabolic disorders, which can be caused by drugs currently used in the treatment of the disease.

Example  4.

In Vitro Pharmacology: Cell Function Analysis

The conditions and methodology of cell function analysis (see literature) are provided in Table 17, and test results for representative compounds of the present invention are presented in Tables 18A and 18B.

The results are expressed as percentage of control specific agonist response obtained in the presence of test compound ((measured specific response / control specific agonist response) × 100).

EC50 values (concentrations that produce half-maximum specific responses) and IC50 values (concentrations that cause half of the maximum inhibition of control specific agonist responses) are Hill equation curve fitting (Y = D + [(A-D)). / (1 + (C / C50) nH)], where Y = specific response, D = minimum specific response, A = maximum specific response, C = compound concentration, and C50 = EC50 or IC50, and nH = slope Factor), measured by non-linear regression analysis of concentration-response curves generated with mean replicates. This analysis was performed using software developed by Cerep (Hill Software) and validated against data generated by the commercial software SigmaPlot ^® 4.0 for Windows ^® (© 1997 by SPSS Inc.).

For antagonists, the apparent dissociation constant (Kb) is the Cheng Prusoff equation (Kb = IC50 / (1+ (A / EC50A)), where A = concentration of the reference agonist in the analysis, and EC50A = EC50 value of the reference agonist) Calculated using.

The results are expressed as percentage of control specific agonist response obtained in the presence of test compound ((measured specific response / control specific agonist response) × 100).

Results are expressed as percentage of control specific binding ((measured specific binding / control specific binding) × 100%) and as Kb value (dissociation constant). Compounds were tested for their affinity for the receptor at a concentration of 1 × 10 ⁻⁶ M. .

EC50 values (concentrations that produce half-maximum specific responses) and IC50 values (concentrations that cause half of the maximum inhibition of control specific agonist responses) are Hill equation curve fitting (Y = D + [(A-D)). / (1 + (C / C50) nH)], where Y = specific response, D = minimum specific response, A = maximum specific response, C = compound concentration, and C50 = EC50 or IC50, and nH = slope Factor), measured by non-linear regression analysis of concentration-response curves generated with mean replicates.

This analysis was performed using software developed by Cerep (Hill Software) and validated against data generated by the commercial software SigmaPlot ^® 4.0 for Windows ^® (© 1997 by SPSS Inc.).

For antagonists, the apparent dissociation constant (Kb) is the Cheng Prusoff equation (Kb = IC50 / (1+ (A / EC50A)), where A = concentration of the reference agonist in the analysis, and EC50A = EC50 value of the reference agonist) Calculated using.

[Table 18a]

[Table 18b]

Exemplary compound 24 showed a unique functional profile by combining partial agonism at the dopamine D2 receptor and antagonism at the serotonin 5-HT6 receptor. In addition, the compounds demonstrated favorable agonist properties at the 5-HT1A receptor, partially agonist properties at the D3 receptor, and antagonist properties at the 5-HT2A receptor. Such properties indicate the possibility of combining antipsychotic effects, which depend on the regulation of the dopaminergic system, with precognitive, antianxiety and antidepressant activity, mainly due to restoring the proper balance of serotonin functional delivery.

Example  5.

Behavioral test of the mouse

Antipsychotic Activity in Mice

Potential antipsychotic activity of Compound 24, which is representative of the psychotic model of mice, associated with inducing locomotor overexpression by administering a substance causing psychosis-dizocilpin, was tested. The ability of the test compound to eliminate this effect is a measure of potential antipsychotic activity.

animal

Male CD-1 mice, in groups of 15, polycarbonate in an environmentally controlled laboratory (ambient temperature 22-20 ° C .; relative humidity 50-60%; 12:12 light: dark cycle, lit at 8:00) Groups were bred for 2-3 days in a Makrolon type 3 cage (size 26.5 x 15 x 42 cm). Standard laboratory food (Ssniff MZ) and filtered water were provided freely. On the day before the experiment the equipment producing "white noise" was turned on for 30 minutes and the mice were weighed accurately to 1 g units. Animals were randomly assigned to treatment groups. All experiments were performed by two observers who did not know the treatment applied between 9:00 and 14:00 in separate groups of animals. Mice were used only once and slaughtered immediately after the experiment.

Disocil pin Induced exercise overexpression

Motor activity was recorded on an Opto M3 multi-channel activity monitor (MultiDevice Software v.1.3, Columbus Instruments). Mice were individually placed in plastic cages (22 × 12 × 13 cm) for a 30 minute habituation period, and then the crossing (movement) of each channel was counted every 5 minutes data recording for 1 hour. After examining each mouse the cage was washed with 70% ethanol. Drugs were administered to 10 mice per treatment group. Test compounds were provided 30 minutes before the experiment. Dizocilpin was administered 30 minutes before the test.

Test compound

Test compounds were prepared by the suspension in a 1% aqueous solution of Tween 80, and diszocilpin was dissolved in distilled water just before administration. An injection volume of 10 ml / kg was used and all compounds were administered intraperitoneally (ip).

C57BL / 6J mouse's tail Suspension  Test

Within 24 hours before the experiment, animals were habituated to experimental conditions. To do this, mice in the home cage were transferred to the lab for 15 minutes while maintaining the lighting and "white noise" characteristic of the experiment.

The experimental procedure was based on the method of Steru et al. (The tail suspension test: a new method for screening antidepressants in mice, Psychopharmacology 85, 367-370, 1985). An automated device (Kinder Scientific) was used. After 1 hour acclimation in low light in the laboratory, mice were administered the test compound intraperitoneally (3 or more selected doses).

After a certain time after the administration of the test compound, the mouse tail was suspended by tape to an aluminum hook connected to the strain gauge. The mouse was positioned so that the base of the tail of the mouse was aligned with the bottom of the hook. This positioning was found to reduce the propensity of the mouse to raise its tail during the test. In order to record the number of times (events) each subject enters evasive behavior (streggling episodes), duration of events, and average intensity of each event during a 6 minute test session, a strain gauge connected to the computer software is Any movement by the mouse was detected. The following settings were used in all experiments: threshold 0,20 Newton, off delay 30 msec.

Four-Plate Testing in Swiss Albino Mice

Within 24 hours before the experiment, animals were habituated to experimental conditions. To do this, mice in the home cage were transferred to the lab for 15 minutes while maintaining the lighting and "white noise" characteristic of the experiment.

A four-plate test (BIOSEB, France) was performed in a bottomed cage (25 x 18 x 16 cm) with four identical rectangular metal plates (8 x 11 cm) separated from each other with a gap of 4 mm. The top of the cage was covered by a transparent perspex lid that prevents escape behavior. The plate was connected to a device capable of producing electric shock. Inhibits the animal's motivation to explore new environments by electrical foot shock (0.8 mA, 0.5 s) each time the animals are individually placed in an experimental cage and after a 15-second habituation period, moving from one plate to the other during the 1 minute test session. It was. This action is referred to as 'punished crossing', followed by a three second shock interval, during which the animal can move the plate without being shocked. The measurement of the anti-anxiety activity of the compound was the number of "punished crossings" during the 1-minute test period with adjoining from one plate.

Rat  Behavioral test

animal

Male Wistar rats (Charles River, Sulzfeld, Germany) without drug administration of 250-400 g body weight in four groups, in an environmentally controlled laboratory (ambient temperature 21-23 ° C; relative humidity 50-60%) 12:12 light: dark cycle, lit at 7:00) bred in a polycarbonate macron cage (size 380 x 200 x 590 mm). Tap water and standard laboratory chow (Labofeed H, WPIK, Kcynia, Poland) were supplied randomly.

Two weeks before the start of the experiment, animals were sent to the Animal Research Unit of the Institute of Psychiatry and Neurology. During these two weeks all rats were repeatedly accustomed to the presence of the experimenter (handling) and injection of saline. Rats were accurately weighed to 1 g units on the day before the experiment. Animals were randomly assigned to treatment groups. All experiments were performed between 9:00 and 15:00 in separate groups of animals. The test compound was administered intraperitoneally (i.p.) in 2 ml / kg injection volumes at three or more selected doses. The control group was administered the appropriate carrier (vehiculum).

Animals were used only once and euthanized immediately after the experiment.

Rat Conflict  Test ( Vogel ( Vogel ) Test)

Animals were habituated to test conditions 24 hours before the experiment. To do this, rats in the home cage were transferred to the laboratory for 15 minutes while maintaining the lighting and "white noise" characteristic of the experiment.

Tests were performed using the monitoring system TSE Systems by the modified method described by Vogel et al. ( Psychopharmacologia , 21 (1), 8-12, 1971).

The system consisted of a polycarbonate cage (size 26.5 x 15 x 42 cm) with a grid layer made of stainless steel bars and a beverage container containing tap water. The experimental chambers (2) were connected by means of a control chassis to the PC software and the device generating the electrical shock. The experiment lasted 3 days. On the first day of the experiment, rats were individually placed in an experimental cage equipped with a beverage container and allowed to acclimate to the test chamber for 10 minutes. After the acclimation period, the animals were isolated from the water for 24 hours and then placed in the test chamber for an additional 10-minute acclimation period, during which time the beverage containers were freely accessible. The rats were then allowed to have a one hour free drinking session in their home cage. After an additional 24 hour water isolation period, rats were placed back in the test chamber after the test compound administration. Data recording started immediately after the first lick, and every 20 licks the rats were punished with electrical shock (0.5 mA, lasting 1 second). Impulses were released through the outlet of the beverage container. When drinking when the impulse was released, the rat was shocked. The number of licking and shock received throughout the 5-minute experiment session was automatically recorded.

Disocil pin  ( MK -801) -derived PPI  Deficit Reversal

Leading pulse suppression ( PPI ) evaluation

The PPI instrument consists of eight acoustic starter chambers (SR-LAB, San Diego Instruments, San Diego, CA, USA). Each chamber consists of a plexiglass cylinder (8,9 cm diameter x 20 cm long) based on the plexiglass frame in a sound attenuated, ventilated enclosure. Background noise and acoustic stimulation were provided through a loudspeaker mounted 24 cm above the animal. The startle response, which reflects the movement of the animal in the cylinder upon acoustic stimulation, was detected by a piezoelectric transducer mounted under the flame. Stimulation input and response recordings were controlled by SR-LAB software. Test sessions started with a 5-minute acclimation period. Over the entire session, the chamber lights were turned on and the background white noise was set to 70 dB. To get the rats familiar with the experimental process, the test session included three initial staging stimuli (intensity: 120 dB, duration: 40 ms). Initial stimulation followed by 60 experiments (6 × 10 experiments) in any order.

10 background experiments (B) related to the presentation of the simulated stimulus (intensity: 70 dB, duration: 40 ms),

Two types (2 x 10) of preceding pulse experiments (PP) (84 dB or 90 dB, 20 ms) containing only the preceding pulse stimulus,

10 pulse experiments (P) (120 dB, 40 ms) containing only pulse starting stimulation,

Two types (2 x 10) of pre-pulse and pulse analysis (PP-P) involving a 120-dB, 40 ms pulse stimulus (P) following 100 ms followed by a preceding pulse (84 dB or 90 dB, 20 ms). ).

The average interval between experiments was 22.5 seconds (range: 15-30 seconds). This interval was randomized by SR-LAB software. The starting response was measured for 100 ms after the start of the last experimental stimulus. For each type of stimulus, startle amplitudes were averaged over 10 experiments. The magnitude of the PPI was calculated as the percentage of inhibition of the star amplitude in the pulse experiment (treated as 100%) according to the following equation: [(starttle amplitude in the P experiment-starttle amplitude in the PP-P experiment) / star in the P experiment Frame amplitude] × 100%. The starter response to three initial stimuli of 120 dB intensity was excluded from statistical analysis.

Disocil pin  ( MK -801) -derived PPI  Deficit Reversal

Test compound

Compound 24 was administered intraperitoneally with a suspension in a 1% aqueous solution of Tween 80 60 minutes prior to the test at a 2 ml / kg injection volume. Dizocilpin was dissolved in saline immediately prior to dosing and administered intraperitoneally in an injection volume of 1 ml / kg 15 minutes before session.

Representative Compound 24 showed broad antipsychotic activity. It was active in the diszocilpin-induced translocation overexpression test in mice, demonstrating its potential in the treatment of positive symptoms of schizophrenia, as well as in the diszocilin (MK-801) -induced PPI deficiency test in rats, This is in the process of evaluating the ability to treat information filtering (size of cognitive deficits) and attention deficits, which are fundamental to the pathological mechanism of schizophrenia. Activity in prior pulse suppression (PPI) tests is due to the identification of disorders modeled in animals and disorders occurring in humans, and hence their relatively high conversion in clinical effects, and in particular does not result in any side effects. At dosage, it has certain values due to low efficiency in eliminating this type of obstruction by currently available antipsychotic drugs (Porsolt RD et al . , J. Pharmacol . Exp . Ther ., 333 (3), 632- 8, 2010). Compound 24 is well suited for detecting substances that have potential antidepressant activity, ie activity in tail suspension testing in mice, as well as potential anti-anxiety activity, ie activity in mice's four-plate tests or fat's conflict drinking tests (vogels). Had activity in the established model. Beyond purely antipsychotic effects, such broad pharmacological activity is a particularly desirable property of current antipsychotic drugs because of the complexity of clinical conditions associated with schizophrenia, including depression and anxiety.

Claims (16)

A compound of formula (IA)

And pharmaceutically acceptable salts thereof,
here
R ¹ is benzyl unsubstituted or substituted with a halogen atom, —OH, or C ₁ -C ₃ -alkyl; or
Phenylsulfonyl unsubstituted or substituted with a halogen atom, -OH or C ₁ -C ₃ -alkyl in the phenyl ring,
G ¹ represents a piperazine moiety of the formula

here
n is 3 or 4,
m is 1,
A ¹ is phenyl unsubstituted or substituted with one substituent selected from the group consisting of a halogen atom, -OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl;
A moiety selected from the group consisting of 3,4-dihydroquinolin-2 ( 1H ) -one-yl, 1,4-benzodioxanyl and benzofuranyl, which is linked through a carbon atom of a benzene ring ; or
Imidazolidin-2-one-yl linked via a nitrogen atom;
To represent. The method according to claim 1, G ¹ A ¹ of the moiety is phenyl unsubstituted or substituted with one substituent selected from the group consisting of a halogen atom, -OH, C ₁ -C ₃ -alkyloxy, and phenyl; A moiety selected from the group consisting of 3,4-dihydroquinolin-2 ( 1H ) -one-yl, 1,4-benzodioxanyl and benzofuranyl, which is linked through a carbon atom of a benzene ring ; Or imidazolidin-2-one-yl linked via a nitrogen atom. The method according to claim 1, G ¹ A ¹ of the moiety is phenyl unsubstituted or substituted with one substituent selected from the group consisting of a halogen atom, -OH, C ₁ -C ₃ -alkyloxy, -CONH ₂ and phenyl; A moiety selected from the group consisting of 3,4-dihydroquinolin-2 ( 1H ) -one-yl, 1,4-benzodioxanyl and benzofuranyl, which is linked through a carbon atom of a benzene ring To represent. The compound of any one of claims 1-3, wherein A ¹ represents 3,4-dihydroquinolin-2 (1 H ) -on-yl. The compound of any one of claims 1-3, wherein A ¹ represents unsubstituted phenyl. The compound of claim 1 or 3, wherein A ¹ represents phenyl substituted with one substituent selected from the group consisting of a halogen atom, —OH, C ₁ -C ₃ -alkyloxy, —CONH _2, and phenyl. The compound of claim 6, wherein the substituent of the phenyl ring is selected from the group consisting of halogen atom, C ₁ -C ₃ -alkyloxy and -CONH ₂ . 8. The compound of claim 1, wherein R ¹ represents unsubstituted phenylsulfonyl. 9. 8. The compound of claim 1, wherein R ¹ represents unsubstituted benzyl. 9. 8. The compound of claim 1, wherein R ¹ represents benzyl substituted with a halogen atom, preferably fluorine or chlorine. The group of claim 1, consisting of:
7- [3- [4- (1-benzylindol-4-yl) piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one
7- (4- (4- (1-benzyl-1H-Indol-4-yl) piperazin-1-yl) butoxy) -3,4-dihydroquinolin-2 (1H) -one
7- [3- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H-quinoline- 2-on
7- [3- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H-quinoline- 2-on
7- [3- [4- [1-[(3-hydroxyphenyl) methyl] indol-4-yl] piperazin-1-yl] -propoxy] -3,4-dihydro-1H-quinoline- 2-on
7- [3- [4- [1- (m-tolylmethyl) indol-4-yl] piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one
4- (4- (3-phenoxypropyl) piperazin-1-yl) -1- (phenylsulfonyl) -1H- Indole
4- (4- (3- (4-fluorophenoxy) propyl) piperazin-1-yl) -1- (phenylsulfonyl) -1H-indole
4- (4- (3- (2- (1-methylethoxy) phenoxy) propyl) piperazin-1-yl) -1- (phenyl-sulfonyl) -1H- Indole
7- [3- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] propoxy] -3,4-dihydro-1H-quinolin-2-one
7- (4- (4- (1- (phenylsulfonyl) -1H-Indol-4-yl) piperazin-1-yl) butoxy) -3,4-dihydroquinolin-2 (1H) -one
4- (4- (3- (benzofuran-6-yloxy) propyl) piperazin-1-yl) -1- (phenylsulfonyl) -1H- Indole
2- [3- [4- (1-benzylindol-4-yl) piperazin-1-yl] propoxy] benzamide
7- [4- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2 -On
2- [3- [4- [1-[(2-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide
7- [4- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2 -On
2- [3- [4- [1-[(3-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide
7- [4- [4- [1-[(4-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2 -On
2- [3- [4- [1-[(4-fluorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide
7- [4- [4- [1-[(3-chlorophenyl) methyl] indol-4-yl] piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinoline-2- On
2- [3- [4- [1-[(3-chlorophenyl) methyl] indol-4-yl] piperazin-1-yl] propoxy] -benzamide
1- (benzenesulfonyl) -4- [4- (4-phenoxybutyl) piperazin-1-yl] indole
1- (benzenesulfonyl) -4- [4- [4- (4-fluorophenoxy) butyl] piperazin-1-yl] -indole
1- (benzenesulfonyl) -4- [4- [4- (2-isopropoxyphenoxy) butyl] -piperazin-1-yl] indole
2- [3- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] propoxy] -benzamide
2- [4- [4- [1- (benzenesulfonyl) indol-4-yl] piperazin-1-yl] butoxy] -benzamide
And pharmaceutically acceptable salts and solvates thereof. The compound of formula (IA) according to any one of claims 1 to 11 for use as a medicament. A pharmaceutical composition comprising a compound of formula (IA) according to any one of claims 1 to 11 as active ingredient in combination with a pharmaceutically acceptable carrier (s) and / or excipient (s). The formula (IA) according to any one of claims 1 to 11 for use in a method of treating and / or preventing a central nervous system disorder associated with dopamine and / or serotonin and / or noradrenaline delivery. Of compounds. The method of claim 14, wherein the central nervous system disorder comprises: schizophrenia; Schizoaffective disorder; Schizophrenic disorders; Delusional syndrome and other psychotic conditions associated with and not related to taking psychoactive substances; Emotional disorders; Bipolar disorder; Manic; depression; Anxiety disorders of various etiologies; Stress response; Consciousness disorder; coma; Delirium of alcoholic or other etiology; Aggression; Psychomotor nervousness and other behavioral disorders; Sleep disorders of various etiologies; Withdrawal syndrome of various etiologies; Addiction; Pain syndrome of various etiologies; Poisoning with psychoactive substances; Disorders of the brain circulation of various etiologies; Mental and physical disorders of various etiologies; Transition disorders; Dissociation disorder; Dysuria; Autism and other developmental disorders, including nocturnal enuresis, stuttering, tics; Various types of cognitive disorders including Alzheimer's disease; And psychopathological symptoms in the course of other diseases of the central and peripheral nervous system and neurological disorders. A pivot associated with serotonin and dopamine functional delivery of a mammal, comprising administering a pharmaceutically effective amount of a compound of formula (IA) according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 13 Methods of treating and / or preventing nervous system disorders.